Depression may result from a functional predominance of central, muscarinic cholinergic neurotransmission compared with aminergic neurotransmission. The objective sleep disturbances which frequently accompany depression, such as short REM latency, increased REM density, and, perhaps, reduced Delta (Stage 3&4) sleep, are consistent with this hypothesis. This grant supports a focused clinical/preclinical research program exploring the role of cholinergic, muscarinic mechanisms in both the clinical pathophysiology of depression and the basic physiology of sleep. Our original finding that cholinergic, muscarinic agonists induce REM sleep faster in depressed patients than normal controls has been replicated in 5 studies with arecoline and 2 studies with RS 86. If funded, we will extend our previous studies with the Cholinergic REM Induction Test (CRIT) by using pilocarpine instead of arecoline. Based upon our finding that M2 receptor agonists in medial pontine reticular formation (mPRF) induce REM sleep in cats, we will explore the role of Ml and M2 receptors in the regulation of REM sleep. In man we will study the pharmacological effects biperiden (a relatively selective Ml antagonist), RS 86 (a relatively selective MI agonist), and pilocarpine (a mixed Ml/M2 agonist) on normal human sleep. Based upon our preliminary results that scopolamine has antidepressant effects, we will conduct the first controlled, double blind study of the effect of an anticholinergic agent (biperiden) in depression. In animals, we will extend our studies with the Flinders Sensitive Line (FSL) of rats, which has been bred for supersensitivity to cholinergic agonists, increased muscarinic receptor density, behavioral characteristics of depression, and short REM latency and increased REM time. We will explore the anatomic distribution of Ml and M2 receptors and the effects of scopolamine upon EEG power in the delta band in the FSL rats. Following upon our demonstration that cholinergic terminals from the lateral dorsal tegmentum and pedunculopontine group go to the mPRF sites where M2 and mixed Ml/M2 agonists induce REM sleep, we will determine other projections of cholinergic cells to medial thalamus, lateral geniculate nucleus, and caudal medulla. Finally, we will explore the anatomic and muscarinic receptor subtype (Ml or M2) specificity for REM induction in cats.